Updates: The most complete version of this article is available at the following location http://intjhumnutrfunctmed.org/ Copyrights: Copyright © 2015 by author(s) and International College of Human Nutrition and Functional Medicine www.ICHNFM.org Free access: Freely available and distributable with all content, text, and image rights reserved by author(s) and ICHNFM. Citation: Vasquez A. Translating Microbiome (Microbiota) and Dysbiosis Research into Clinical Practice: The 20-Year Development of a Structured Approach that Gives Actionable Form to Intellectual Concepts. Int J Hum Nutr Funct Med 2015;v3(q2):p1

International Journal of Human Nutrition and Functional Medicine www.ICHNFM.org

Photos © by Dr Vasquez, 2013-2015

Mini-Review ● Continuing Education • Microbiome • Dysbiosis • Infectious Disease

Translating Microbiome (Microbiota) and Dysbiosis Research into

Clinical Practice: The 20-Year Development of a Structured

Approach that Gives Actionable Form to Intellectual Concepts

Alex Vasquez DC ND DO FACN

Experience and Perspectives Many years ago when I published my first books1,2 and articles3

detailing "dysbiosis", the word could hardly be found in the

Medline index, the topic was controversial at best and ethereal

at worst, the term "microbiome" (first published in French in

1949 and in English in 1988) was virtually unknown, and I spent

most of the time and space in my lectures and articles

substantiating and defending the condition's existence. These

days, everyone is talking about microbiome, dysbiosis, "leaky

gut" (thanks largely to Leo Galland MD), and my 1996 article

on “Silent Infections and Gastrointestinal Dysbiosis" has been

downloaded at least 4,000 times and is one of the top 1% most

popular articles on Academia.edu.4 In the preparation of my

dysbiosis lecture at a major functional medicine conference in

2010, I found that only 180 Medline articles indexed the term

“dysbiosis”, and now—slightly less than five years later—more

than 1,200 articles index that term. Obviously, the dysbiosis

concept has become better known to the point of actually being

popular, but this does not mean that clinicians understand what

to do with it. A recent article from the June 2015 issue of Nature

Medicine perfectly summarized this discrepancy between

microbiota research and clinical action: "In the three years since

the completion of the first phase of the Human Microbiome

Project, the number of scientific papers linking the microbes

that live in our gut to diseases ranging from diabetes and colitis

to anxiety and depression has grown exponentially. Yet, these

tantalizing connections have yielded few benefits from a

therapeutics standpoint."5 To the extent that this information is

being integrated into clinical practice at all, the current level of

practical application is a bit indelicate and cumbersome beyond

the most commonly repeated advice of advocating probiotics,

avoiding antibiotics, perhaps delving into using botanical

antimicrobials and laboratory testing. Breath testing (an

insensitive test for only one subtype of gastrointestinal

dysbiosis) and microbiologic testing have become popular to the

point of overuse as doctors grapple for clinical clues.

(Noteworthy in the conversation on functional laboratory testing

is that one functional medicine laboratory in particular used

inaccurate proprietary microbe-identification methods to extract

millions of dollars of patient and physician money only to

deliver innumerable wasted hours in patient suffering and

ICHNFM has many videos on the topics of dysbiosis,

persistent infections, and dysbiotic clinical conditions such

as fibromyalgia at www.Vimeo.com/ICHNFM

"Dysbiosis" is an important concept, but doctors cannot treat concepts.

We have to define, describe, and deconstruct the microbes, molecules, and mechanisms into their components, then rebuild a conceptual scaffold and intellectual structure that becomes a useful tool that, with study and experience, can be used in a clinical setting to effective benefit.

International Journal of Human Nutrition and Functional Medicine www.IntJHumNutrFunctMed.Org 2015 Final PDF

physician confusion due to misleading and worthless [e.g.,

"parasite present: taxonomy unavailable"] laboratory

information.6) So, despite the bloom in research and the

exponential public awareness of dysbiosis, much progress still

needs to be made in order to help clinicians—and ultimately

patients—better appreciate, assess, optimize and maintain

microbiotal health—eubiosis.

Clinical Importance The priority is to understand the role of dysbiosis in clinical

disease; patients are suffering day-by-day and hour-by-hour

because of microbial colonization, bacterial allergy, reactive

arthritis, systemic inflammation, fibromyalgia, insulin

resistance, neurocognitive impairments, autoimmunity, and

other manifestations of dysbiosis. The basic science and clinical

research data on these various phenomena is crystal clear and

intellectually sound but is rarely delivered in a manageable

manner so that time-pressured clinicians can perceive the

information in an interconnected context that expedites clinical

application in patient assessment and treatment. Personally, I

have generally approached clinical care with a sense of urgency,

for altruistic reasons and because I know the experience of being

persistently ill—in my case, the situation lasted for seven years

and still occasionally recurs, as discussed later.

Dysbiosis-Triggered Illness: Deconstructing the Phenomena and Helping Our Patients Dysbiotic illness can ultimately be understood as a

manifestation of human intolerance of the total microbial load

(TML) and more specifically the total dysbiotic load (TDL)

which is only one part of the total inflammatory load (TIL),

alternately described as the total impairment load—that is, the

total load of physiologic, biochemical, and psychosocial

burdens that promote inflammation or any type of

metabolic/physiologic/mental impairment. As I have said for

many years, dysbiosis is a disease state best described as a "bad

relationship" wherein neither the host nor the microbe(s) are

unilaterally "at fault" but rather that they are—for a variety of

modifiable and nonmodifiable reasons—currently

incompatible. Conceptualizing dysbiotic illnesses as a

relationship rather than as an infection—an extension of the

acute infection model wherein the microbe is presumed guilty

gives us three major areas of intervention:

immunorestoration, tolerogenic or adaptive, antimicrobial.

Clinical pathophysiology of dysbiosis-induced disease: The total microbial load communicates to the human body in general and the innate/adaptive immune systems specifically from various locations via specific molecules, which then are "combinatorially summarized" in conjunction with the patient's physiologic profile—including genetic makeup, nutritional status, xenobiotic load, sleep and stress status—to produce a pattern of clinical manifestations. Doctors are trained to diagnose and treat the resulting prototypic pattern rather than the problems contributing to the pattern. Image from cover and text of Vasquez A. Human Microbiome and Dysbiosis in Clinical Disease. Published, copyrighted ©, trademarked ® by Dr Alex Vasquez and International College of Human Nutrition and Functional Medicine 2015. [ISBN 1512360295 / 9781512360295]

International Journal of Human Nutrition and Functional Medicine www.IntJHumNutrFunctMed.Org 2015 Final PDF

Personal Experience I did not become an expert in dysbiosis entirely by choice; I had

to become so in order to literally save my own life and preserve

my own health. The year was 1995, the idea of "leaky gut" was

new and ridiculed (in contrast to its wide acceptance today), and

the entire concept of functional medicine had only been

announced just a few years prior. Thanks to mostly to

Metchnikoff, the naturopathic profession, a handful of

allopathic doctors, and a few scattered and vintage medical

articles, we had some vague ideas about dysbiosis but very few

details with which to understand it better, let alone treat it

effectively. In this case, I am discussing gastrointestinal

dysbiosis, which is the prototype but obviously only one of the

eight location-based subtypes of dysbiosis.

I remember the exact day and moment that it all started. What

began with the typical "brain fog" later progressed to physical

inertia, multiple chemical sensitivity / environmental

intolerance (MCS/EI), and progressive immediate-onset food

allergies, most of which were frustratingly unidentified except

for soy lecithin—of note, 1996 was the first year of genetically

manipulated (GM) soy in the US. I was also progressively

lymphopenic and had remarkable responses to parenteral

vitamins, especially vitamin B12 (improved mental clarity) and

folic acid (resolution of progressive lymphopenia). At this time,

I was finishing chiropractic college, starting naturopathic

college, and harvesting gems from every seminar, book, and

audiocassette I could find, notably from Bland, Galland, Gaby

and Wright. With new access to the internet, I scoured the earlier

versions of Medline and spent my evenings and weekends in the

medical libraries at Oregon Health Science University in

Portland and University of Washington in Seattle. I started

compiling and publishing articles, and my main research

interests at the time—other than studying everything nutrition

and trying to find solutions to my own mysterious illnesses—were rheumatology and hemochromatosis.7

Following graduation and licensure, I opened a clinical

practice in Seattle, and later I was also invited to teach

Orthopedics and Rheumatology at Bastyr University. The

responsibility of teaching these courses gave me reason to dive

even deeper into the research and to begin articulating and

giving structure to what almost always starts as inklings and

impressions. Slowly, I started to understand dysbiosis, its

various permutations, and the variances of effect that different

microbes could have, either in isolation or in combination—what I would later elucidate as combinatorial dysbiosis8 and

continue to refine on an almost daily and regular basis.9

With effort and reflection, obscurity morphed into clarity. If

all we had to work with is the laboratory result above, this alone

would have been sufficient to explain and solve all my health

problems within hours; I have this level of understanding now,

but only after studying the topic—not simply for academic

reasons or in a cursory manner, but with some sense of personal

urgency—for twenty years. The main findings of the results

above are the Citrobacter freundii and the Klebsiella

pneumoniae, and additional finding on this same result was that

of markedly elevated fecal beta-glucuronidase. With years of

trial and error and a high degree of certainty based on personal

experience backed by a massive review of the research

literature, I would interpret the above results as follows:

• The mental and physical fatigue I experienced were due

mostly to hydrogen sulfide (H2S) produced by the

Citrobacter freundii. H2S is a mitochondrial toxin and thus

a neurotoxin, thereby explaining the fatigue, and it also

chelates cobalamin, thereby explaining the response to

vitamin B12, indicative of vitamin B12 deficiency, which

was also contributing to the fatigue. Constipation was

another problem that was not only miserable, but which also

promoted the persistence of the dysbiosis and which was

caused by the gut-paralyzing effect of H2S.

• The multiple chemical sensitivity / environmental

intolerance (MCS/EI) was due to impaired cytochrome

p450 detoxification secondary to endotoxin in general and

the O antigen of Klebsiella pneumoniae in particular.

Additively and synergistically, the elevated fecal beta-

glucuronidase was deconjugating whatever little cytochrome

p450 detoxification was taking place, leading to the inability

to clear and thus the accumulation of ambient chemicals and

internal toxins that could not be oxidized for conjugation;

notice the dual effect of endotoxin-mediated blockade of

cytochrome p450 along with increased enterohepatic

recycling due to the elevated fecal beta-glucuronidase. The

folate deficiency and resultant lymphopenia are presumed

due to a combination of malabsorption and increased

utilization; at this time I also had an increased

lactulose:mannitol ratio and dramatically elevated caffeine

clearance with horrid benzoate conjugation.

• Immediate-onset food allergies were due to the increased

intestinal permeability and immune activation, both of which

can be blamed on elevated gastrointestinal endotoxin.

During this time, I gained personal physician heal thyself

experience with practically innumerable nutrients, botanicals,

and a few antimicrobial drugs; I also appreciated—and was

ultimately cured by—my (in)famous vitamin C purge: first-

morning consumption of two cups of coffee (peristalsis

stimulant) and ~30 grams of vitamin C with the resulting

osmotic laxative and exaggerated migratory motor complex

providing gastrointestinal housecleaning par excellence.

Conclusions With the compilation of personal experiences and ongoing

research from thousands of clinicians and basic scientists, we

collectively have the knowledge and tools available to assess

and alleviate dysbiotic illnesses in their various forms. The

twilight of the idiopathic era and the dawn of new possibilities

in health and healthcare continue to be progressively

illuminated.10

Dr Vasquez's test results from ~1996: Everything is obvious when you know the answer; sample study guide and CE exam questions are available: http://ow.ly/O15vd

International Journal of Human Nutrition and Functional Medicine www.IntJHumNutrFunctMed.Org 2015 Final PDF

Free-access videos related to the topics of this article

https://vimeo.com/117742117

https://vimeo.com/123715277

https://vimeo.com/125074159

https://vimeo.com/129841003

https://vimeo.com/116470021 https://vimeo.com/109318556

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International Journal of Human Nutrition and Functional Medicine www.IntJHumNutrFunctMed.Org 2015 Final PDF

History of this publication: This article was written and illustrated by Dr Alex Vasquez; editorial critiques and peer reviews were provided by a quorum of IJHNFM reviewers. Kind review was also provided by external laboratory specialists. Publication does not imply endorsement by all members of IJHNFM Editorial Review Board.

1. Vasquez A. Integrative Rheumatology. Integrative and Biological Medicine Research and Consulting, 2006. *

2. Vasquez A. Musculoskeletal Pain: Expanded Clinical Strategies. Institute for Functional Medicine, 2008. * Updated in 2014 as Naturopathic Rheumatology v3.5 cited below.

3. Vasquez A. Multifocal dysbiosis: Pathophysiology, relevance for inflammatory and autoimmune diseases, and treatment with nutritional and botanical interventions. Naturopathy Digest 2006 Jun http://www.ichnfm.org/faculty/vasquez/reprints/2006_multifocal_dysbiosis.html

4. Vasquez A. Nutritional and Botanical Treatments Against “Silent Infections” and Gastrointestinal Dysbiosis, Commonly Overlooked Causes of Neuromusculoskeletal Inflammation and Chronic Health Problems. Nutritional Perspectives 2006 Jan. http://ow.ly/O0Wau

5. de Vrieze J. Microbiome models, on computers and in lab dishes, see progress. Nature Medicine 2015 June; 21: 543–544 www.nature.com/articles/nm0615-543

6. Gingras BA, Duncan SB, Scheuller NJ, Schreckenberger PC. Assessment of diagnostic accuracy of recently introduced DNA stool screening test. International Journal of Human Nutrition and Functional Medicine 2014;v2(q1);p1 http://ow.ly/O2eRE

7. Vasquez A. Musculoskeletal disorders and iron overload disease: comment on the American College of Rheumatology guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. Arthritis Rheum. 1996 Oct;39(10):1767-8 http://www.ncbi.nlm.nih.gov/pubmed/8843875

8. Vasquez A. Naturopathic Rheumatology v3.5. International College of Human Nutrition and Functional Medicine, 2014. [ISBN 0990620425 / 978-0990620426] http://www.amazon.com/dp/0990620425

9. Vasquez A. Human Microbiome and Dysbiosis in Clinical Disease. International College of Human Nutrition and Functional Medicine, 2015. [ISBN 1512360295 / 9781512360295] https://www.createspace.com/5518130

10. Vasquez A. Idiopathic versus Multifactorial: Twilight of the Idiopathic Era and the Dawn of New Possibilities in Health and Healthcare. Naturopathy Digest 2006 naturopathydigest.com/archives/2006/mar/idiopathic.php with minor edits made in 2010 and 2014 http://ow.ly/O2fW6

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